Estradiuol (E2) replacement therapy (ERT) in menopausal women has protective effects on a variety of age-related diseases, including osteoporosis, cardiovascular diseases, age-related memory impairments, and development of dementia. However, ERT, even with progestin co- treatment, induces precancerous changes in the tissues of the breast and uterus. A new group of non-steroidal estrogens, deemed Selective Estrogen Receptor Modulators (SERMs) has been developed as a possible alternative to ERT but without the adverse proliferative effects on breast and endometrial tissues, while retaining some of the positive effects of E2. Yet, despite the well-documented efficacy of these compounds in peripheral target tissues, their influence in the brain, and especially upon cognitive function, is not known. Clearly brain and cognitive effects of SERMs must be understood in order to determine their desirability as an alternative to ERT in hypoestrogenic women. We will use the ovariectomized rhesus monkey as a model of human low-estrogen conditions, such as menopause, to examine the effects of SERMs on female cognition. This project will first determine whether the SERMs tamoxifen and raloxifene are E2 agonists or E2 antagonists in a variety of cognitive domains in Ovariectomized female rhesus monkeys. Monkeys will be repeatedly tested with a computerized touch- screen system on a battery of four memory and attentional tasks while undergoing E2, SERMs, or placebo treatments. Specific Aim 2ill use the same battery of tasks to determine whether SERMs, in the presence of E2, act as E2 antagonists on cognitive function. Specific Aim 3 will use positron emission tomography (PET) and the glucose metabolic tracer [18F]fluorodeoxyglucose (18F FDG) to determine whether E2 increases activation of specific brain regions following performance on the cognitive task most improved by ERT. Specific Aim 1 will determine whether SERMs mimic E2 in enhancing object recognition memory, attention, and working memory, while impairing spatial memory functions in ovariectomized female rhesus monkeys. Specific Aim 2 will determine whether SERMs, in the presence of E2, act a sE2 antagonists in cognitive function/ Specific Aim 3 will use PET and the 18F FDG tracer to evaluate the relationships between rCMRglc, ERT, and cognitive performance on a specific task. These data in the rhesus monkey will provide valuable information on the efficacy of SERMs on female cognition and will help in evaluating the risks and benefits of using these compounds in hypoestrogenic women.